rs543675502

Variant names:

• chr2-110123988-G-A
• rs543675502
• NM_001128178.3:c.1837C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001128178.3(NPHP1):​c.1837C>T​(p.Arg613Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R613H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: NPHP1 NM_001128178.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.210
• Publications: 3 publications found

Genes affected

NPHP1 (HGNC:7905): (nephrocystin 1) This gene encodes a protein with src homology domain 3 (SH3) patterns. This protein interacts with Crk-associated substrate, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures. Mutations in this gene cause familial juvenile nephronophthisis type 1, a kidney disorder involving both tubules and glomeruli. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NPHP1 Gene-Disease associations (from GenCC):

• Joubert syndrome with renal defect

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• nephronophthisis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14628252).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128178.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	NM_001128178.3	MANE Select	c.1837C>T	p.Arg613Cys	missense	Exon 20 of 20	NP_001121650.1	O15259-2
	NPHP1	NM_000272.5		c.2005C>T	p.Arg669Cys	missense	Exon 20 of 20	NP_000263.2
	NPHP1	NM_207181.4		c.2002C>T	p.Arg668Cys	missense	Exon 20 of 20	NP_997064.2	O15259-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	ENST00000445609.7	TSL:1 MANE Select	c.1837C>T	p.Arg613Cys	missense	Exon 20 of 20	ENSP00000389879.3	O15259-2
	NPHP1	ENST00000316534.8	TSL:1	c.2005C>T	p.Arg669Cys	missense	Exon 20 of 20	ENSP00000313169.4	O15259-4
	NPHP1	ENST00000393272.7	TSL:1	c.2002C>T	p.Arg668Cys	missense	Exon 20 of 20	ENSP00000376953.3	O15259-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251488 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461752 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111886

Other (OTH) AF: 0.000116 AC: 7 AN: 60388

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000731 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Joubert syndrome with renal defect;C1855681:Nephronophthisis 1;C4551559:Senior-Loken syndrome 1 (1)
-	1	-	Nephronophthisis (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.079	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.21
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.14
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.11
MutPred		0.34		Loss of disorder (P = 0.0572)
MVP		0.76
MPC		0.36
ClinPred		0.20	T
GERP RS		3.6
Varity_R		0.085
gMVP		0.18
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs543675502; hg19: chr2-110881565; COSMIC: COSV57212042; COSMIC: COSV57212042;